The ongoing epidemic of obesity in the United States represents a public health emergency that remains unchecked and without specific therapy. To design specific treatments to prevent and treat obesity, we must first understand the mechanisms that regulate feeding and energy expenditure in order to identify potential therapeutic targets. In this proposal, entitled, Role of the lateral hypothalamic area in leptin action, we will analyze leptin-regulated neural pathways in the lateral hypothalamic area (LHA) that contribute to body energy homeostasis, incentive, and activity. During the previous funding period, we developed and utilized genetic mouse models to demonstrate that LHA LepRb neurons directly innervate OX neurons and the VTA, and are required to modulate orexin action, the mesolimbic DA system and energy balance (in addition to analyzing some related leptin-regulated neural circuitry). In this renewal application, we will employ existing and novel genetic systems to understand the sufficiency of this circuit for a variety of parameters. We will also understand distinct and overlapping roles for subpopulations of LHA LepRb neurons for the control of orexin, the midbrain DA system, and feeding, as well as defining the circuits and neural mechanisms underlying the regulation of these important processes. These studies will enable us to understand the mechanisms by which the LHA leptin action contributes to overall leptin action, energy balance, and aspects of neural function that are crucial for hedonically-driven overeating. This information will in turn lay the groundwork for understanding mechanisms by which feeding may be regulated, which is crucial as we seek to determine the pathogenesis of, and potential therapeutic targets for the ongoing epidemic of obesity.